GENETICS OF PRIMARY IMMUNODEFICIENCY IN FINLAND

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http://urn.fi/URN:ISBN:978-951-51-4784-4
Title: GENETICS OF PRIMARY IMMUNODEFICIENCY IN FINLAND
Author: Trotta, Luca
Contributor: University of Helsinki, Faculty of Biological and Environmental Sciences
Doctoral Programme in Integrative Life Science
Thesis level: Doctoral dissertation (article-based)
Belongs to series: Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis - URN:ISSN:2342-317X
Abstract: Primary Immunodeficiency (PIDs) categorize a broad and heterogeneous group of inborn immunity errors. Despite being generally quite rare, PIDs collectively account for consistent morbidity and mortality. Currently, more than 350 monogenic PIDs have been recognised to embody clinical phenotypes ranging from life-threatening infections to autoimmune/inflammatory diseases, allergies and/or malignancy. Many PIDs display genetic and allelic heterogeneity with an overlap of symptoms among different syndromes, often making diagnoses challenging. In the past few years, advancements in genomic technologies have revolutionised the world of genetic testing, and currently, next-generation sequencing (NGS)-based approaches are widely applied to routine genetic diagnostics of human disorders. Among the different methods, whole-exome sequencing (WES) proved highly efficient in revealing the genetic variants behind rare disorders. To further depict the genetics of PIDs, a WES-based approach was carried out, targeting the possible disease-causing variants in Finnish subjects lacking a clinical diagnosis. The cohort included patients with a clinical suspicion of immune or/and haematological disorders (n= 212). In the first study, a Finnish founder mutation in the AICDA gene was identified in patients affected by hyper-IgM syndrome type 2 (HIGM2). The disease is a primary antibody deficiency characterised by early-onset recurrent infections, autoimmunity and an absence/low levels of IgG, IgA and IgE but elevated/normal levels of IgM. The retrieved ancestral founder allele is significantly enriched in Finns compared to other European populations (38.56-fold) and has accounted for all HIGM2 cases diagnosed in Finns thus far. In the second study, biallelic ADA2 mutations that cause a deficiency of adenosine deaminase 2 (DADA2) were identified in seven PID patients, all sharing one of the causal variants, which were significantly enriched in Finns (3.31-fold). DADA2 was originally associated with systemic autoinflammation, polyarteritis nodosa-type vasculitis and mild immunodeficiency. Only a fraction of the identified DADA2 patients presented with vasculopathies. In addition, recurrent haematological manifestations are noted, and for the first time, the occurrence of lymphoproliferation is described for some of the patients, expanding the phenotypic spectrum of DADA2. Finally, novel causal variants in telomere biology disorders (TBDs)-associated genes were identified in three families with heterogeneous phenotypes that lacked the classic clinical pathognomonic signs of telomeropathies. The phenotypes ranged from mild signs of Dyskeratosis congenita (DKC) to SCID. The genetic diagnosis was confirmed by an assessment of shortened telomere lengths in patients. In addition, the spectrum of TBD-associated phenotypes was enlarged, showing variable degrees of cytopenia in some patients. This work attests to the validity of clinical WES testing to identify rare disease-causing variants despite the heterogeneous and/or atypical clinical presentations of PIDs. The achievement of a genetic diagnosis allowed for updating the spectrum of reported phenotypes as well as including atypical clinical presentations that might have otherwise remained undiagnosed. In addition, the enrichment of some rare PID-causing mutations in Finland has been depicted, highlighting the correlation of the population history with the distribution of rare deleterious variants of clinical relevance.Primary Immunodeficiency (PIDs) categorize a broad and heterogeneous group of inborn immunity errors. Despite being generally quite rare, PIDs collectively account for consistent morbidity and mortality. Currently, more than 350 monogenic PIDs have been recognised to embody clinical phenotypes ranging from life-threatening infections to autoimmune/inflammatory diseases, allergies and/or malignancy. Many PIDs display genetic and allelic heterogeneity with an overlap of symptoms among different syndromes, often making diagnoses challenging. In the past few years, advancements in genomic technologies have revolutionised the world of genetic testing, and currently, next-generation sequencing (NGS)-based approaches are widely applied to routine genetic diagnostics of human disorders. Among the different methods, whole-exome sequencing (WES) proved highly efficient in revealing the genetic variants behind rare disorders. To further depict the genetics of PIDs, a WES-based approach was carried out, targeting the possible disease-causing variants in Finnish subjects lacking a clinical diagnosis. The cohort included patients with a clinical suspicion of immune or/and haematological disorders (n= 212). In the first study, a Finnish founder mutation in the AICDA gene was identified in patients affected by hyper-IgM syndrome type 2 (HIGM2). The disease is a primary antibody deficiency characterised by early-onset recurrent infections, autoimmunity and an absence/low levels of IgG, IgA and IgE but elevated/normal levels of IgM. The retrieved ancestral founder allele is significantly enriched in Finns compared to other European populations (38.56-fold) and has accounted for all HIGM2 cases diagnosed in Finns thus far. In the second study, biallelic ADA2 mutations that cause a deficiency of adenosine deaminase 2 (DADA2) were identified in seven PID patients, all sharing one of the causal variants, which were significantly enriched in Finns (3.31-fold). DADA2 was originally associated with systemic autoinflammation, polyarteritis nodosa-type vasculitis and mild immunodeficiency. Only a fraction of the identified DADA2 patients presented with vasculopathies. In addition, recurrent haematological manifestations are noted, and for the first time, the occurrence of lymphoproliferation is described for some of the patients, expanding the phenotypic spectrum of DADA2. Finally, novel causal variants in telomere biology disorders (TBDs)-associated genes were identified in three families with heterogeneous phenotypes that lacked the classic clinical pathognomonic signs of telomeropathies. The phenotypes ranged from mild signs of Dyskeratosis congenita (DKC) to SCID. The genetic diagnosis was confirmed by an assessment of shortened telomere lengths in patients. In addition, the spectrum of TBD-associated phenotypes was enlarged, showing variable degrees of cytopenia in some patients. This work attests to the validity of clinical WES testing to identify rare disease-causing variants despite the heterogeneous and/or atypical clinical presentations of PIDs. The achievement of a genetic diagnosis allowed for updating the spectrum of reported phenotypes as well as including atypical clinical presentations that might have otherwise remained undiagnosed. In addition, the enrichment of some rare PID-causing mutations in Finland has been depicted, highlighting the correlation of the population history with the distribution of rare deleterious variants of clinical relevance.
URI: URN:ISBN:978-951-51-4784-4
http://hdl.handle.net/10138/278894
Date: 2019-01-24
Subject: Genetics
Rights: This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited.


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